Roger Bedimo, MD; Song Zhang, PhD; Henning Drechsler, MD; Pablo Tebas, MD; Naim Maalouf, MD

1. Risk of Osteoporotic Fractures Associated with Cumulative Exposure to Tenofovir and Other Antiretroviral Agents Roger Bedimo, MD; Song Zhang, PhD; Henning Drechsler, MD; Pablo Tebas, MD; Naim Maalouf, MD

2. Osteoporotic Fractures among HIV-Infected Patients: Role of ART • Decreased bone mineral density is increasingly reported in the aging HIV-positive population. • Odds of osteoporosis are elevated in HIV-infected vs. uninfected1,2, and in ART users vs. non-users1 • Tenofovir exposure was shown to be associated with a significantly greater decrease in bone mineral density than stavudine3, and abacavir4 • The risk of osteoporotic fractures (OF) associated with cumulative (PY) exposure to tenofovir vs. other antiretroviral agents has never been explored 1Brown and Qaqish AIDS 2006,20:2165-2174.; 2Triant et al, JCEM. 2008,93:3499-3504 3Gallant et al., JAMA. 2004;292(2):191-201. 4McComsey G. JID 2011;203(12):1791-801

3. Methods: Data Source, Predictors and Outcome Measures • Data Source: Veterans Affairs’ Clinical Case Registry; HIV patients in pre-HAART (’88-’95) and HAART eras (’96-’09). • Predictors: • Antiretroviral exposure: PY of exposure to NRTIs (TDF, ABC, AZT or D4T), NNRTI, boosted PI. • Age, Race, Smoking, BMI, type 2 diabetes, HCV co-infection (by ICD-9 codes or antibody +), Chronic kidney disease: Estimated GFR<60 by MDRD • Gender not included in the model; The population is >98% male. • Outcome:Incident osteoporotic fracture defined as any: • Vertebral fractures (ICD-9 codes 805.2 through 805.7), Hip fractures (820.0 through 820.9), or Wrist fractures (814.0, 814.1, 813.4 and 813.5)

4. Results: Study Population, Treatment Exposure and Events • Two separate analyses were conducted, including: • All patients enrolled in CCR from 1988 to 2009. • Patients enrolled in the HAART era only: from 1996 to 2009. • Cumulative exposure to each separate ARV or ARV class, from first administration to censure date: • 1) development of the first OF episode ; 2) discontinuation of the ARV; 3) last recorded patient encounter; 4) December 31st, 2009 (date of censure of the dataset). • Cox survival models of association of ARV exposure & OF: • 1) Univariate analysis; • 2) MV Model 1: Controlling for CKD, age, race, tobacco use, DM, BMI & HCV; 3) MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

5. Results: Study Population, Follow-Up Time and Events *defined for this study as first vertebral, wrist or hip fracture during follow-up

6. Risk Factors among Patients with and without Osteoporotic Fracture *Classified only by ICD-9 codes. Laboratory values not extracted

7. Age-adjusted Rates of Osteoporotic Fractures (Entire Cohort) 8 7 6 Vertebral 5 Hip Fracture Rate (per 1,000 patient-years) Wrist 4 Total 3 General population1 2 1Data from Triant V, et al., JCEM 2008;93: 3499–3504 1 0 18-29 30-39 40-49 50-59 60-69 ≥70 Age at Cohort Entry (Years)

8. Factors Predicting Osteoporotic Fracture in HIV Patients

9. Antiretroviral Exposure and Risk of Osteoporotic Fractures: 1988-2009 MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

10. Antiretroviral Exposure and Risk of Osteoporotic Fractures: 1988-2009 Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

11. What Happened in the HAART Era? • Higher % of patients on ARVs, low viremia. • Increased survival (and time at risk) and increased fracture rates Pre-HAART Era: 1.61 Events/1000 PY HAART Era: 4.09 Events/1000 PY

12. Antiretroviral Exposure and Risk of Osteoporotic Fractures: HAART Era MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

13. Antiretroviral Exposure and Risk of Osteoporotic Fractures: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

14. Interaction Between TDF and PI Exposure for OF Risk: HAART Era • Concomitant exposure to both TDF and rPI associated with a greater OF risk than exposure to either TDF without rPI or rPI without TDF Hazard Ratio

15. Exposure to Specific Protease Inhibitors and OF Risk: HAART Era MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

16. Exposure to Specific Protease Inhibitors and OF Risk: HAART Era MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

17. Exposure to Specific Protease Inhibitors and OF Risk: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

18. Discussion – Entire Study Period • Overall, antiretroviral exposure is associated with a non-significant OF risk after controlling for OF risk factors. • HR for cumulative ART exposure is modest compared to other fracture risk factors: White race, advancing age and smoking • Cumulative exposure to TDF and boosted PI are each associated with modest increase in fracture risk in univariate analysis, but not after controlling for fracture risk factors. • Significant increase in fracture rates in the HAART era • Cumulative ART exposure likely does not account for the increased risk in the HAART era

19. Discussion – HAART Era - I • Fracture risk associated with cumulative exposure to TDF remains significant after controlling for other OF risk factors and concomitant ARV used. • Cumulative exposure to boosted PI is also associated with increased OF risk after controlling for other OF risk factors, but not after controlling for concomitant ARVs. • There was an interaction between TDF and boosted PI use. • Greater fracture rates, higher (significant) HR for TDF and rPI in the HAART era could be due to longer survival, and exclusion of most patients with no Rx, mono-dual Rx

20. Discussion – HAART Era - II • Among PIs, LPV/RTV is associated with an increased OF risk. Exposure to ATV, NFV or IDV were not associated with increased OF risk. • While these could be explained by concomitant use of RTV with LPV, neither RTV alone nor boosted ATV or IDV were associated with increased risk.

21. Strengths and Limitations • Large sample size (more than 56,000 patients; more than 900 with fracture events) • Uniform data collection on exposures and outcomes across VA system, including pre-HAART and HAART eras. • Our study is a retrospective cohort study. • Osteoporotic fracture events not ascertained (only ICD-9 code used – validated in other VA studies) • Bone mineral density is not evaluated. Fractures cannot be proven to be osteoporotic in nature.

22. Acknowledgements • Study funded by VA MERIT grant I01 CX000418-01A1 • Thanks to the VA Center for Quality Management for access to CCR data and material support • Thanks to IAS for giving us the opportunity to share our work